A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte

Abstract

The functions of epithelial tissues are dictated by the types, abundance and distribution of the differentiated cells they contain. Attempts to restore tissue function after damage require knowledge of how physiological tasks are distributed among cell types, and how cell states vary between homeostasis, injury-repair and disease. In the conducting airway, a heterogeneous basal cell population gives rise to specialized luminal cells that perform mucociliary clearance. Here we perform single-cell profiling of human bronchial epithelial cells and mouse tracheal epithelial cells to obtain a comprehensive census of cell types in the conducting airway and their behaviour in homeostasis and regeneration. Our analysis reveals cell states that represent known and novel cell populations, delineates their heterogeneity and identifies distinct differentiation trajectories during homeostasis and tissue repair. Finally, we identified a novel, rare cell type that we call the 'pulmonary ionocyte', which co-expresses FOXI1, multiple subunits of the vacuolar-type H-ATPase (V-ATPase) and CFTR, the gene that is mutated in cystic fibrosis. Using immunofluorescence, modulation of signalling pathways and electrophysiology, we show that Notch signalling is necessary and FOXI1 expression is sufficient to drive the production of the pulmonary ionocyte, and that the pulmonary ionocyte is a major source of CFTR activity in the conducting airway epithelium.

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

“…In CF, lung disease begins in the small airways where the CFTR protein is primarily expressed [26,27]. In contrast, for treatment of surfactant protein deficiencies, the target cells are located in the parenchyma, mainly in alveolar type 2 (AT-2) cells.…”

“…For example, in PCD the ciliated cells of the trachea and primary bronchi are more affected, compared with the more distal cells affected in CF. While targeting stem cells within the lung would be advantageous, there is currently poor consensus on the identity and location of the lung stem cell population [27] and compelling evidence that each lung compartment has its own progenitor cell type and niche [28]. Thus, there is currently no single lung stem cell that can be targeted for all disease applications.…”

“…As mentioned before, alternate genetic lung diseases may originate from different cell types and in different regions of the lung [26,27]. This represents a challenge to develop platform gene therapies for multiple diseases, since both the vector tropism and delivery method will have to be fine-tuned to meet specific disease needs.…”

“…CD34 + cells), the same cannot often be said for in-vivo gene therapy for lung or liver. Although there is currently no consensus on the identity of a single ‘lung stem cell’ [26,27], once identified, that stem cell will still require a vector capable of transducing it in an in-vivo setting. The profound differences in developmental and adult lung biology between mice and humans [89] have not made the development of suitable vectors for in-vivo stem cell targeting any easier.…”

Reaction combination opens up 3D molecular diversity for drug discovery

“…The power of these reactions has been demonstrated in numerous syntheses of complex natural products 1,2 . However, the scope of cycloadditions is limited to certain combinations of starting materials, which has restricted their use for making libraries of compounds in drugdiscovery programs 3 .…”